SummaryDespite considerable advances in drug discovery, resistance to anticancer chemotherapy confounds the effective treatment of patients. Cancer cells can acquire broad cross-resistance to mechanistically and structurally unrelated drugs. P-glycoprotein (Pgp) actively extrudes many types of drugs from cancer cells, thereby conferring resistance to those agents. The central tenet of my work is that Pgp, a universally accepted biomarker of drug resistance, should in addition be considered as a molecular target of multidrug-resistant (MDR) cancer cells. Successful targeting of MDR cells would reduce the tumor burden and would also enable the elimination of ABC transporter-overexpressing cancer stem cells that are responsible for the replenishment of tumors. The proposed project is based on the following observations:
- First, by using a pharmacogenomic approach, I have revealed the hidden vulnerability of MDRcells (Szakács et al. 2004, Cancer Cell 6, 129-37);
- Second, I have identified a series of MDR-selective compounds with increased toxicity toPgp-expressing cells
(Turk et al.,Cancer Res, 2009. 69(21));
- Third, I have shown that MDR-selective compounds can be used to prevent theemergence of MDR (Ludwig, Szakács et al. 2006, Cancer Res 66, 4808-15);
- Fourth, we have generated initial pharmacophore models for cytotoxicity and MDR-selectivity (Hall et al. 2009, J Med Chem 52, 3191-3204).
I propose a comprehensive series of studies that will address thefollowing critical questions:
- First, what is the scope of MDR-selective compounds?
- Second, what is their mechanism of action?
- Third, what is the optimal therapeutic modality?
Extensive biological, pharmacological and bioinformatic analyses will be utilized to address four major specific aims. These aims address basic questions concerning the physiology of MDR ABC transporters in determining the mechanism of action of MDR-selective compounds, setting the stage for a fresh therapeutic approach that may eventually translate into improved patient care.

Despite considerable advances in drug discovery, resistance to anticancer chemotherapy confounds the effective treatment of patients. Cancer cells can acquire broad cross-resistance to mechanistically and structurally unrelated drugs. P-glycoprotein (Pgp) actively extrudes many types of drugs from cancer cells, thereby conferring resistance to those agents. The central tenet of my work is that Pgp, a universally accepted biomarker of drug resistance, should in addition be considered as a molecular target of multidrug-resistant (MDR) cancer cells. Successful targeting of MDR cells would reduce the tumor burden and would also enable the elimination of ABC transporter-overexpressing cancer stem cells that are responsible for the replenishment of tumors. The proposed project is based on the following observations:
- First, by using a pharmacogenomic approach, I have revealed the hidden vulnerability of MDRcells (Szakács et al. 2004, Cancer Cell 6, 129-37);
- Second, I have identified a series of MDR-selective compounds with increased toxicity toPgp-expressing cells
(Turk et al.,Cancer Res, 2009. 69(21));
- Third, I have shown that MDR-selective compounds can be used to prevent theemergence of MDR (Ludwig, Szakács et al. 2006, Cancer Res 66, 4808-15);
- Fourth, we have generated initial pharmacophore models for cytotoxicity and MDR-selectivity (Hall et al. 2009, J Med Chem 52, 3191-3204).
I propose a comprehensive series of studies that will address thefollowing critical questions:
- First, what is the scope of MDR-selective compounds?
- Second, what is their mechanism of action?
- Third, what is the optimal therapeutic modality?
Extensive biological, pharmacological and bioinformatic analyses will be utilized to address four major specific aims. These aims address basic questions concerning the physiology of MDR ABC transporters in determining the mechanism of action of MDR-selective compounds, setting the stage for a fresh therapeutic approach that may eventually translate into improved patient care.

Max ERC Funding

1 499 640 €

Duration

Start date: 2012-01-01, End date: 2016-12-31

Project acronymACTIVATION OF XCI

ProjectMolecular mechanisms controlling X chromosome inactivation

Researcher (PI)Joost Henk Gribnau

Host Institution (HI)ERASMUS UNIVERSITAIR MEDISCH CENTRUM ROTTERDAM

Call DetailsStarting Grant (StG), LS2, ERC-2010-StG_20091118

SummaryIn mammals, gene dosage of X-chromosomal genes is equalized between sexes by random inactivation of either one of the two X chromosomes in female cells. In the initial phase of X chromosome inactivation (XCI), a counting and initiation process determines the number of X chromosomes per nucleus, and elects the future inactive X chromosome (Xi). Xist is an X-encoded gene that plays a crucial role in the XCI process. At the start of XCI Xist expression is up-regulated and Xist RNA accumulates on the future Xi thereby initiating silencing in cis. Recent work performed in my laboratory indicates that the counting and initiation process is directed by a stochastic mechanism, in which each X chromosome has an independent probability to be inactivated. We also found that this probability is determined by the X:ploïdy ratio. These results indicated the presence of at least one X-linked activator of XCI. With a BAC screen we recently identified X-encoded RNF12 to be a dose-dependent activator of XCI. Expression of RNF12 correlates with Xist expression, and a heterozygous deletion of Rnf12 results in a marked loss of XCI in female cells. The presence of a small proportion of cells that still initiate XCI, in Rnf12+/- cells, also indicated that more XCI-activators are involved in XCI. Here, we propose to investigate the molecular mechanism by which RNF12 activates XCI in mouse and human, and to search for additional XCI-activators. We will also attempt to establish the role of different inhibitors of XCI, including CTCF and the pluripotency factors OCT4, SOX2 and NANOG. We anticipate that these studies will significantly advance our understanding of XCI mechanisms, which is highly relevant for a better insight in the manifestation of X-linked diseases that are affected by XCI.

In mammals, gene dosage of X-chromosomal genes is equalized between sexes by random inactivation of either one of the two X chromosomes in female cells. In the initial phase of X chromosome inactivation (XCI), a counting and initiation process determines the number of X chromosomes per nucleus, and elects the future inactive X chromosome (Xi). Xist is an X-encoded gene that plays a crucial role in the XCI process. At the start of XCI Xist expression is up-regulated and Xist RNA accumulates on the future Xi thereby initiating silencing in cis. Recent work performed in my laboratory indicates that the counting and initiation process is directed by a stochastic mechanism, in which each X chromosome has an independent probability to be inactivated. We also found that this probability is determined by the X:ploïdy ratio. These results indicated the presence of at least one X-linked activator of XCI. With a BAC screen we recently identified X-encoded RNF12 to be a dose-dependent activator of XCI. Expression of RNF12 correlates with Xist expression, and a heterozygous deletion of Rnf12 results in a marked loss of XCI in female cells. The presence of a small proportion of cells that still initiate XCI, in Rnf12+/- cells, also indicated that more XCI-activators are involved in XCI. Here, we propose to investigate the molecular mechanism by which RNF12 activates XCI in mouse and human, and to search for additional XCI-activators. We will also attempt to establish the role of different inhibitors of XCI, including CTCF and the pluripotency factors OCT4, SOX2 and NANOG. We anticipate that these studies will significantly advance our understanding of XCI mechanisms, which is highly relevant for a better insight in the manifestation of X-linked diseases that are affected by XCI.

Max ERC Funding

1 500 000 €

Duration

Start date: 2011-04-01, End date: 2016-03-31

Project acronymEARLYWARNING

ProjectGeneric Early Warning Signals for Critical Transitions

Researcher (PI)Marten Scheffer

Host Institution (HI)WAGENINGEN UNIVERSITY

Call DetailsAdvanced Grant (AdG), LS8, ERC-2010-AdG_20100317

SummaryAbrupt shifts occasionally reshape complex systems in nature ranging in scale from lakes and reefs to regional climate systems. Such shifts sometimes represent critical transitions in the sense that they happen at tipping points where runaway change propels the system towards an alterative contrasting state. Although the mechanism of critical transitions can often be reconstructed in the hindsight, we are virtually unable to predict when they will happen in advance. Simulation models for complex environmental systems are simply not good enough to predict tipping points, and there is little hope that this will change over the coming decades. The proposed project is aimed at developing an alternative way to predict critical transitions. We aim at finding early warning signals for such transitions that are generic in the sense that they work irrespective of the (often poorly known) mechanisms responsible for the tipping points. Mathematical theory indicates that this might be possible. However, although excitement about these ideas is emerging, we are far from having a cohesive theory, let alone practical approaches for predicting critical transitions in large complex systems like lakes, coral reefs or the climate. I will work towards this goal with my team along three lines: 1) Develop a comprehensive theory of early warning signals using analytical mathematical techniques as well as models ranging in character from simple and transparent to elaborate and realistic; 2) Test the theory on experimental plankton systems kept in controlled microcosms; and 3) Analyze data from real systems that go through catastrophic transitions. The anticipated results would imply a major breakthrough in a field of research that is exiting as well as highly relevant to society. If we are successful, it would allow us to anticipate critical transitions even in large complex systems where we have little hope of predicting tipping points on the basis of mechanistic models.

Abrupt shifts occasionally reshape complex systems in nature ranging in scale from lakes and reefs to regional climate systems. Such shifts sometimes represent critical transitions in the sense that they happen at tipping points where runaway change propels the system towards an alterative contrasting state. Although the mechanism of critical transitions can often be reconstructed in the hindsight, we are virtually unable to predict when they will happen in advance. Simulation models for complex environmental systems are simply not good enough to predict tipping points, and there is little hope that this will change over the coming decades. The proposed project is aimed at developing an alternative way to predict critical transitions. We aim at finding early warning signals for such transitions that are generic in the sense that they work irrespective of the (often poorly known) mechanisms responsible for the tipping points. Mathematical theory indicates that this might be possible. However, although excitement about these ideas is emerging, we are far from having a cohesive theory, let alone practical approaches for predicting critical transitions in large complex systems like lakes, coral reefs or the climate. I will work towards this goal with my team along three lines: 1) Develop a comprehensive theory of early warning signals using analytical mathematical techniques as well as models ranging in character from simple and transparent to elaborate and realistic; 2) Test the theory on experimental plankton systems kept in controlled microcosms; and 3) Analyze data from real systems that go through catastrophic transitions. The anticipated results would imply a major breakthrough in a field of research that is exiting as well as highly relevant to society. If we are successful, it would allow us to anticipate critical transitions even in large complex systems where we have little hope of predicting tipping points on the basis of mechanistic models.

Max ERC Funding

2 299 171 €

Duration

Start date: 2011-06-01, End date: 2016-05-31

Project acronymECOSPACE

ProjectEcoSpace: Spatial-Dynamic Modelling of Adaptation Options to Climate Change at the Ecosystem Scale

Researcher (PI)Lars Gerard Hein

Host Institution (HI)WAGENINGEN UNIVERSITY

Call DetailsStarting Grant (StG), SH3, ERC-2010-StG_20091209

SummaryClimate change will necessitate adjustments in ecosystem management in order to maintain the functioning of ecosystems and the supply of ecosystem services. The aim of this project is to develop a spatially explicit, dynamic modelling approach for identifying and analysing adaptation strategies for ecosystem management.
In particular, the project will develop and apply a general, spatial model integrating climate change scenarios, ecosystem dynamics, response thresholds, ecosystem services supply and management options. The scientific innovation of the project lies in the application of an ecosystem services approach to analyse adaptation options, the integration of complex ecosystem dynamics and societal impacts, and the spatially explicit modelling of economic benefits supplied by ecosystems.
The general model will be tested and validated on the basis of three case studies, focussing on: (i) flood protection in the Netherlands; (ii) impacts of climate change in northern Norway; and (iii) optimising land use including production of biofuels stock in Kalimantan, Indonesia. The first two areas are particularly vulnerable to climate change, and the third area is relevant because of its importance as a source of biofuel (palmoil) with associated environmental and social impacts. Each case study will be implemented in collaboration with local and international partners, and will result in the identification of economic efficient, sustainable and equitable local adaptation options.

Climate change will necessitate adjustments in ecosystem management in order to maintain the functioning of ecosystems and the supply of ecosystem services. The aim of this project is to develop a spatially explicit, dynamic modelling approach for identifying and analysing adaptation strategies for ecosystem management.
In particular, the project will develop and apply a general, spatial model integrating climate change scenarios, ecosystem dynamics, response thresholds, ecosystem services supply and management options. The scientific innovation of the project lies in the application of an ecosystem services approach to analyse adaptation options, the integration of complex ecosystem dynamics and societal impacts, and the spatially explicit modelling of economic benefits supplied by ecosystems.
The general model will be tested and validated on the basis of three case studies, focussing on: (i) flood protection in the Netherlands; (ii) impacts of climate change in northern Norway; and (iii) optimising land use including production of biofuels stock in Kalimantan, Indonesia. The first two areas are particularly vulnerable to climate change, and the third area is relevant because of its importance as a source of biofuel (palmoil) with associated environmental and social impacts. Each case study will be implemented in collaboration with local and international partners, and will result in the identification of economic efficient, sustainable and equitable local adaptation options.

Max ERC Funding

759 600 €

Duration

Start date: 2010-11-01, End date: 2015-10-31

Project acronymENCODING IN AXONS

ProjectIdentifying mechanisms of information encoding in myelinated single axons

SummaryA major challenge in neuroscience is to understand how information is stored and coded within single nerve cells (neurons) and across neuron populations in the brain. Nerve cell fibres (axons) are thought to provide the wiring to connect neurons and conduct the electrical nerve impulse (action potential; AP). Recent discoveries, however, show that the initial part of axons actively participates in modulating APs and providing a means to enhance the computational repertoire of neurons in the central nervous system. To decrease the temporal delay in information transmission over long distances most axons are myelinated. Here, we will test the hypothesis that the degree of myelination of single axons directly and indirectly influences the mechanisms of AP generation and neural coding. We will use a novel approach of patch-clamp recording combined with immunohistochemical and ultrastructural identification to develop a detailed model of single myelinated neocortical axons. We also will investigate the neuron-glia interactions responsible for the myelination process and measure whether their development follows an activity-dependent process. Finally, we will elucidate the physiological and molecular similarities and discrepancies between myelinated and experimentally demyelinated single neocortical axons. These studies will provide a novel methodological framework to study central nervous system axons and yield basic insights into myelin physiology and pathophysiology.

A major challenge in neuroscience is to understand how information is stored and coded within single nerve cells (neurons) and across neuron populations in the brain. Nerve cell fibres (axons) are thought to provide the wiring to connect neurons and conduct the electrical nerve impulse (action potential; AP). Recent discoveries, however, show that the initial part of axons actively participates in modulating APs and providing a means to enhance the computational repertoire of neurons in the central nervous system. To decrease the temporal delay in information transmission over long distances most axons are myelinated. Here, we will test the hypothesis that the degree of myelination of single axons directly and indirectly influences the mechanisms of AP generation and neural coding. We will use a novel approach of patch-clamp recording combined with immunohistochemical and ultrastructural identification to develop a detailed model of single myelinated neocortical axons. We also will investigate the neuron-glia interactions responsible for the myelination process and measure whether their development follows an activity-dependent process. Finally, we will elucidate the physiological and molecular similarities and discrepancies between myelinated and experimentally demyelinated single neocortical axons. These studies will provide a novel methodological framework to study central nervous system axons and yield basic insights into myelin physiology and pathophysiology.

SummaryOver the last decades European societies have become more ethnically diverse. However, a more comprehensive understanding of the life course and population dynamics in migrant families is still lacking. Ignoring a large share of the population in studies on family and population dynamics is exclusive and does not reflect reality. My project is first of all innovative in providing a more comprehensive overview of individual life courses of migrants: events in different life domains are linked and full life trajectories are analysed and explained. I will focus not only on the causes but also study the consequences of life course decisions. The second project goal is to explain the effect of migration on intergenerational solidarity and family ties. The analyses will link different phases in the life course as well as different generations. Families of different migrant and native origin will be compared in these parts. Third, I will make unique comparisons between the life course trajectories in the countries of origin and settlement of migrants. Bringing in the perspective of the sending country is original and crucial for understanding to what extent life course choices are related to the integration process in the host society, or to a trend that also occurs in the country of origin. A final major novelty of this project is that different recent data sources are linked within each of the components of the project. The combination of data from the Gender and Generations Survey (GGS), The Integration of the Second Generation (TIES) survey, the PAIRFAM survey, the European Social Survey, the Demographic and Health Surveys and the census, allow for a more complete understanding of the life courses of migrants and population dynamics in migrant families.

Over the last decades European societies have become more ethnically diverse. However, a more comprehensive understanding of the life course and population dynamics in migrant families is still lacking. Ignoring a large share of the population in studies on family and population dynamics is exclusive and does not reflect reality. My project is first of all innovative in providing a more comprehensive overview of individual life courses of migrants: events in different life domains are linked and full life trajectories are analysed and explained. I will focus not only on the causes but also study the consequences of life course decisions. The second project goal is to explain the effect of migration on intergenerational solidarity and family ties. The analyses will link different phases in the life course as well as different generations. Families of different migrant and native origin will be compared in these parts. Third, I will make unique comparisons between the life course trajectories in the countries of origin and settlement of migrants. Bringing in the perspective of the sending country is original and crucial for understanding to what extent life course choices are related to the integration process in the host society, or to a trend that also occurs in the country of origin. A final major novelty of this project is that different recent data sources are linked within each of the components of the project. The combination of data from the Gender and Generations Survey (GGS), The Integration of the Second Generation (TIES) survey, the PAIRFAM survey, the European Social Survey, the Demographic and Health Surveys and the census, allow for a more complete understanding of the life courses of migrants and population dynamics in migrant families.

Max ERC Funding

1 012 800 €

Duration

Start date: 2011-02-01, End date: 2016-08-31

Project acronymGP

ProjectCOMBATING CLIMATE CHANGE: Political economy of Green Paradoxes

Researcher (PI)Cornelius Antonius Adrianus Maria Withagen

Host Institution (HI)STICHTING VU

Call DetailsAdvanced Grant (AdG), SH3, ERC-2010-AdG_20100407

SummaryGreen Paradoxes are defined as the phenomenon that climate change policies can have counterproductive effects. For example, a subsidy on clean energy from renewable resources (solar, wind) will decrease the price at which this energy is supplied. But if the price still exceeds the cost of fossil fuel extraction and given that available stocks will be depleted, the price decrease will speed up the extraction from non-renewable resources, such as oil, that cause CO2 emissions. Hence, instead of delaying extraction the policy enhances initial extraction and emissions. In the design of environmental policy this effect is insufficiently taken into account, because the supply side of the market for fossil fuels is largely neglected.
The principal aim of this research proposal is to critically investigate Green Paradoxes and to come up with sound policy recommendations, taking into account the demand as well as the supply dimension of fossil fuels. Particular attention is paid to a broad and dynamic welfare analysis, allowing for concerns regarding sustainability. Especially relevant for tackling the research question is to provide a closer examination of imperfect competition on the oil market and to distinguish between dirty and clean alternatives for fossil fuel. In addition the proposal is to study the political economy of climate change policy to come up with proposals that not only muster global support but also address the adverse distributional aspects of climate change itself on developing economies and on the poorest of advanced economies who get hardest hit by green taxes. This requires not only the tools of modern political economy, but also the realms of second-best economics and the latest developments in public finance.

Green Paradoxes are defined as the phenomenon that climate change policies can have counterproductive effects. For example, a subsidy on clean energy from renewable resources (solar, wind) will decrease the price at which this energy is supplied. But if the price still exceeds the cost of fossil fuel extraction and given that available stocks will be depleted, the price decrease will speed up the extraction from non-renewable resources, such as oil, that cause CO2 emissions. Hence, instead of delaying extraction the policy enhances initial extraction and emissions. In the design of environmental policy this effect is insufficiently taken into account, because the supply side of the market for fossil fuels is largely neglected.
The principal aim of this research proposal is to critically investigate Green Paradoxes and to come up with sound policy recommendations, taking into account the demand as well as the supply dimension of fossil fuels. Particular attention is paid to a broad and dynamic welfare analysis, allowing for concerns regarding sustainability. Especially relevant for tackling the research question is to provide a closer examination of imperfect competition on the oil market and to distinguish between dirty and clean alternatives for fossil fuel. In addition the proposal is to study the political economy of climate change policy to come up with proposals that not only muster global support but also address the adverse distributional aspects of climate change itself on developing economies and on the poorest of advanced economies who get hardest hit by green taxes. This requires not only the tools of modern political economy, but also the realms of second-best economics and the latest developments in public finance.

SummaryHealth care practitioners face daily questions and make choices regarding the effectiveness and quality of several health technologies (e.g. alternative interventions). On this regard they usually consider meta-analysis; the statistical synthesis of results from relevant experiments. The main drawback of the current state of the art is that meta-analysis focuses on comparing only two alternatives. However, clinicians and scientists need to know the relative ranking of a set of alternative options and not only whether option A is better than B. There is an urgent need to establish and disseminate a robust framework for selecting among many treatment options, possibly after taking into account environmental and genetic interactions. The goal of the proposed project is to provide this by establishing and disseminating a revolutionary evidence synthesis toolkit. Its main methodological vehicle is a flexible statistical framework using Bayesian techniques for multiple-treatments meta-analysis. This will enable the relative ranking of all alternative health care options, will allow comprehensive use of all available data, will improve precision and confidence in the conclusions and will answer methodological questions related to bias. Once established in clinical epidemiology, the tool will be extended to genetic epidemiology to account for multiple genetic markers, environmental factors and effects of treatments. Based on ongoing collaborations with teams undertaking applied health care research I plan to evaluate the new tool empirically in real-life health care problems such as ranking the pharmacological treatments for osteoarthritis, indicating the best treatments for multiple sclerosis and ranking the vaccines for influenza.

Health care practitioners face daily questions and make choices regarding the effectiveness and quality of several health technologies (e.g. alternative interventions). On this regard they usually consider meta-analysis; the statistical synthesis of results from relevant experiments. The main drawback of the current state of the art is that meta-analysis focuses on comparing only two alternatives. However, clinicians and scientists need to know the relative ranking of a set of alternative options and not only whether option A is better than B. There is an urgent need to establish and disseminate a robust framework for selecting among many treatment options, possibly after taking into account environmental and genetic interactions. The goal of the proposed project is to provide this by establishing and disseminating a revolutionary evidence synthesis toolkit. Its main methodological vehicle is a flexible statistical framework using Bayesian techniques for multiple-treatments meta-analysis. This will enable the relative ranking of all alternative health care options, will allow comprehensive use of all available data, will improve precision and confidence in the conclusions and will answer methodological questions related to bias. Once established in clinical epidemiology, the tool will be extended to genetic epidemiology to account for multiple genetic markers, environmental factors and effects of treatments. Based on ongoing collaborations with teams undertaking applied health care research I plan to evaluate the new tool empirically in real-life health care problems such as ranking the pharmacological treatments for osteoarthritis, indicating the best treatments for multiple sclerosis and ranking the vaccines for influenza.

Max ERC Funding

592 500 €

Duration

Start date: 2010-10-01, End date: 2015-12-31

Project acronymINTERIMPACT

ProjectImpact of identified interneurons on cellular network mechanisms in the human and rodent neocortex

Researcher (PI)Gábor Tamás

Host Institution (HI)SZEGEDI TUDOMANYEGYETEM

Call DetailsAdvanced Grant (AdG), LS5, ERC-2010-AdG_20100317

SummaryThis application addresses mechanisms linking the activity of single neurons with network events by defining the function of identified cell types in the cerebral cortex. The key hypotheses emerged from our experiments and propose that neurogliaform cells and axo-axonic cells achieve their function in the cortex through extreme forms of unspecificity and specificity, respectively. The project capitalizes on our discovery that neurogliaform cells reach GABAA and GABAB receptors on target cells through unitary volume transmission going beyond the classical theory which states that single cortical neurons act in or around synaptic junctions. We propose that the spatial unspecificity of neurotransmitter action leads to unprecedented functional capabilities for a single neuron simultaneously acting on neuronal, glial and vascular components of the surrounding area allowing neurogliaform cells to synchronize metabolic demand and supply in microcircuits. In contrast, axo-axonic cells represent extreme spatial specificity in the brain: terminals of axo-axonic cells exclusively target the axon initial segment of pyramidal neurons. Axo-axonic cells were considered as the most potent inhibitory neurons of the cortex. However, our experiments suggested that axo-axonic cells can be the most powerful excitatory neurons known to date by triggering complex network events. Our unprecedented recordings in the human cortex show that axo-axonic cells are crucial in activating functional assemblies which were implicated in higher order cognitive representations. We aim to define interactions between active cortical networks and axo-axonic cell triggered assemblies with an emphasis on mechanisms modulated by neurogliaform cells and commonly prescribed drugs.

This application addresses mechanisms linking the activity of single neurons with network events by defining the function of identified cell types in the cerebral cortex. The key hypotheses emerged from our experiments and propose that neurogliaform cells and axo-axonic cells achieve their function in the cortex through extreme forms of unspecificity and specificity, respectively. The project capitalizes on our discovery that neurogliaform cells reach GABAA and GABAB receptors on target cells through unitary volume transmission going beyond the classical theory which states that single cortical neurons act in or around synaptic junctions. We propose that the spatial unspecificity of neurotransmitter action leads to unprecedented functional capabilities for a single neuron simultaneously acting on neuronal, glial and vascular components of the surrounding area allowing neurogliaform cells to synchronize metabolic demand and supply in microcircuits. In contrast, axo-axonic cells represent extreme spatial specificity in the brain: terminals of axo-axonic cells exclusively target the axon initial segment of pyramidal neurons. Axo-axonic cells were considered as the most potent inhibitory neurons of the cortex. However, our experiments suggested that axo-axonic cells can be the most powerful excitatory neurons known to date by triggering complex network events. Our unprecedented recordings in the human cortex show that axo-axonic cells are crucial in activating functional assemblies which were implicated in higher order cognitive representations. We aim to define interactions between active cortical networks and axo-axonic cell triggered assemblies with an emphasis on mechanisms modulated by neurogliaform cells and commonly prescribed drugs.

SummaryMalignant pleural effusion (MPE) is a significant problem most commonly caused by adenocarcinomas. Although tumors involving the pleura vary in their ability to produce MPE, pathways critical for MPE formation are poorly defined. We have found that mouse tumors harboring mutant (”)KRas produce MPE in mice while tumors without ”KRas do not. LLC and MC38 lung and colon adenocarcinomas, potent inducers of MPE in syngeneic mice, harbor ”KRas that drives constitutive Ras and alternative nuclear factor (NF)-ºB signaling, inflammatory gene expression, and recruitment of specific myeloid cells to the pleural space. In contrast, mouse B16 melanoma and AE17 mesothelioma have wtKRas, lack constitutive Ras/alternative NF-º’ signaling, and are incapable of forming MPE. RNAi-mediated silencing of KRas in MC38 tumors abrogated MPE formation and Ras/alternative NF-º’ activation, while these phenomena were reconstituted in B16 tumors after KRas overexpression. We hypothesize that Ras-activating mutations drive the inflammatory phenotype of adenocarcinomas critical for MPE formation, which is characterized by Ras/alternative NF-ºB activation, inflammatory signalling to host vasculature/immune system, and recruitment of specific myeloid cells, and results in endothelial proliferation/leakiness. To test this hypothesis, we propose to: 1) define the relationship between Ras-activating mutations (RAM) and MPE formation; 2) identify tumor cell Ras-dependent signalling pathways and gene expression signature critical for MPE formation; 3) investigate the host response to tumor cells with RAM that results in MPE; and 4) target Ras and dependent signalling pathways as potential therapy for MPE. Studies will be performed using delivery of mouse/human tumors with/without RAM into the pleura of syngeneic/immunocompromized mice and are likely to yield new insights into the mechanisms of pleural tumor progression and to identify novel approaches to treatment of cancer patients with MPE.

Malignant pleural effusion (MPE) is a significant problem most commonly caused by adenocarcinomas. Although tumors involving the pleura vary in their ability to produce MPE, pathways critical for MPE formation are poorly defined. We have found that mouse tumors harboring mutant (”)KRas produce MPE in mice while tumors without ”KRas do not. LLC and MC38 lung and colon adenocarcinomas, potent inducers of MPE in syngeneic mice, harbor ”KRas that drives constitutive Ras and alternative nuclear factor (NF)-ºB signaling, inflammatory gene expression, and recruitment of specific myeloid cells to the pleural space. In contrast, mouse B16 melanoma and AE17 mesothelioma have wtKRas, lack constitutive Ras/alternative NF-º’ signaling, and are incapable of forming MPE. RNAi-mediated silencing of KRas in MC38 tumors abrogated MPE formation and Ras/alternative NF-º’ activation, while these phenomena were reconstituted in B16 tumors after KRas overexpression. We hypothesize that Ras-activating mutations drive the inflammatory phenotype of adenocarcinomas critical for MPE formation, which is characterized by Ras/alternative NF-ºB activation, inflammatory signalling to host vasculature/immune system, and recruitment of specific myeloid cells, and results in endothelial proliferation/leakiness. To test this hypothesis, we propose to: 1) define the relationship between Ras-activating mutations (RAM) and MPE formation; 2) identify tumor cell Ras-dependent signalling pathways and gene expression signature critical for MPE formation; 3) investigate the host response to tumor cells with RAM that results in MPE; and 4) target Ras and dependent signalling pathways as potential therapy for MPE. Studies will be performed using delivery of mouse/human tumors with/without RAM into the pleura of syngeneic/immunocompromized mice and are likely to yield new insights into the mechanisms of pleural tumor progression and to identify novel approaches to treatment of cancer patients with MPE.